<br>乙型肝炎病毒 S 抗原转运抑制寡核苷酸聚合物、STOPS、分子的作用机制,Molecular Therapy - Nucleic Acids

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乙型肝炎病毒 S 抗原转运抑制寡核苷酸聚合物、STOPS、分子的作用机制
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2021-12-11 , DOI: 10.1016/j.omtn.2021.12.013
C Cheng Kao ₁ , Yuchun Nie ₁ , Suping Ren ₁ , N Tilani T S De Costa ₁ , Rajendra K Pandey ₁ , Jin Hong ₁ , David B Smith ₁ , Julian A Symons ₁ , Leonid Beigelman ₁ , Lawrence M Blatt ₁

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慢性乙型肝炎的功能性治愈需要消除乙型肝炎病毒（HBV）编码的表面抗原（HBsAg），这种抗原会抑制免疫反应。STOPS 是硫代磷酸化单链寡核苷酸，含有新型化学成分，可显著降低 HBV 感染肝细胞产生的 HBsAg。STOPS 分子 ALG-10000 在细胞内发挥作用，以降低多个 HBV 编码分子的水平。然而，它不结合 HBV 分子。发现一种与 ALG-10000 偶联的亲和树脂可结合来自携带复制 HBV 的肝细胞的几种蛋白质。沉默靶向宿主因子 SRSF1、HNRNPA2B1、GRP78 （HspA5）、RPLP1 和 RPLP2 的 RNA 降低了 HBsAg 水平和其他 HBV 分子，这些分子同时被 STOPS 降低。宿主蛋白 RPLP1/RPLP2 和 GRP78 在膜蛋白的翻译、蛋白质折叠和降解中发挥作用。ALG-10000 以及 RPLP1/2 和 GRP78 的敲低降低了 HBsAg 的水平，增加了它们的泛素化和蛋白酶体降解。仅当 HBsAg 与 HBV 调节序列一起表达时，GRP78、RPLP1 和 RPLP2 才会影响 HBsAg 的产生，这表明 HBV 已经进化到与这些 STOPS 相互作用分子结合。HBV 感染细胞中 HBsAg 水平的 STOPS 抑制是通过隔离 HBsAg 正常表达和折叠所需的细胞蛋白来实现的。

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Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules

A functional cure of chronic hepatitis B requires eliminating the hepatitis B virus (HBV)-encoded surface antigen (HBsAg), which can suppress immune responses. STOPS are phosphorothioated single-stranded oligonucleotides containing novel chemistries that significantly reduce HBsAgs produced by HBV-infected liver cells. The STOPS molecule ALG-10000 functions inside cells to reduce the levels of multiple HBV-encoded molecules. However, it does not bind HBV molecules. An affinity resin coupled with ALG-10000 was found to bind several proteins from liver cells harboring replicating HBV. Silencing RNAs targeting host factors SRSF1, HNRNPA2B1, GRP78 (HspA5), RPLP1, and RPLP2 reduced HBsAg levels and other HBV molecules that are concomitantly reduced by STOPS. Host proteins RPLP1/RPLP2 and GRP78 function in the translation of membrane proteins, protein folding, and degradation. ALG-10000 and the knockdowns of RPLP1/2 and GRP78 decreased the levels of HBsAg and increased their ubiquitination and proteasome degradation. GRP78, RPLP1, and RPLP2 affected HBsAg production only when HBsAg was expressed with HBV regulatory sequences, suggesting that HBV has evolved to engage with these STOPS-interacting molecules. The STOPS inhibition of HBsAg levels in HBV-infected cells occurs by sequestering cellular proteins needed for proper expression and folding of HBsAg.

更新日期：2021-12-11

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